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Optimal clinical management of children receiving the ketogenic diet: recommendations of the international ketogenic diet study group

Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xSPECIAL REPORTOptimal clinical management of children receiving theketogenic diet: Recommendations of the InternationalKetogenic Diet Study Group∗Eric H. Kossoff, †Beth A. Zupec-Kania, ‡Per E. Amark, §Karen R. Ballaban-Gil,¶A. G. Christina Bergqvist, #Robyn Blackford, ∗∗Jeffrey R. Buchhalter,††Roberto H. Caraballo, ‡‡J. Helen Cross, ‡Maria G. Dahlin, §§Elizabeth J. Donner,¶¶Joerg Klepper, §Rana S. Jehle, ##Heung Dong Kim, §§Y. M. Christiana Liu,∗∗∗Judy Nation, #Douglas R. Nordli, Jr., †††Heidi H. Pfeifer, ‡‡‡Jong M. Rho,§§§Carl E. Stafstrom, †††Elizabeth A. Thiele, ∗Zahava Turner, ¶¶¶Elaine C. Wirrell,###James W. Wheless, ∗∗∗∗Pierangelo Veggiotti, ∗Eileen P. G. Vining and The CharlieFoundation, and the Practice Committee of the Child Neurology Society∗The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; †Children’s Hospital of Wisconsin, Milwaukee,Wisconsin, U.S.A.; ‡Karolinska Hospital, Stockholm, Sweden; §Montefiore Medical Center, Bronx, New York, USA;¶Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.; #Children’s Memorial Hospital, Chicago,Illinois, U.S.A.; ∗∗Phoenix Children’s Hospital, Phoenix, Arizona, U.S.A.; ††Hospital de Pediatr´ıa Prof. Dr. Juan P.Garrahan, Buenos Aires, Argentina; ‡‡Institute of Child Health and Great Ormond Street Hospital for ChildrenNHS Trust, London, United Kingdom; §§Hospital for Sick Children, Toronto, Canada; ¶¶Children’s Hospital,Aschaffenburg, Germany; ##Severance Children’s Hospital, Seoul, South Korea; ∗∗∗Royal Children’s Hospital,Melbourne, Australia; †††Massachusetts General Hospital, Boston, Massachusetts, U.S.A.; ‡‡‡Barrow NeurologicInstitute, Phoenix, Arizona, U.S.A.; §§§University of Wisconsin – Madison, Madison, Wisconsin, U.S.A.; ¶¶¶MayoClinic, Rochester, Minnesota, U.S.A.; ###Le Bonheur Children’s Medical Center, Memphis, Tennessee, U.S.A.; and∗∗∗∗University of Pavia, Pavia, Italyment regarding the clinical management of the KD.The ketogenic diet (KD) is an established, effec-Subsequently endorsed by the Practice Commit-tive nonpharmacologic treatment for intractabletee of the Child Neurology Society, this resultantchildhood epilepsy. The KD is provided differentlymanuscript addresses issues such as patient selec-throughout the world, with occasionally signifi-tion, pre-KD counseling and evaluation, specific di-cant variations in its administration. There exists aetary therapy selection, implementation, supple-need for more standardized protocols and manage-mentation, follow-up management, adverse eventment recommendations for clinical and researchmonitoring, and eventual KD discontinuation. Thisuse. In December 2006, The Charlie Foundationpaper highlights recommendations based on bestcommissioned a panel comprised of 26 pediatricevidence, including areas of agreement and contro-epileptologists and dietitians from nine countriesversy, unanswered questions, and future research.with particular expertise using the KD. This groupWORDS: Children,Consensus,was created in order to create a consensus state-Epilepsy, Ketogenic.
The ketogenic diet (KD) is a nonpharmacologic treat-
(Stafstrom & Rho, 2004; Kossoff & McGrogan, 2005;
ment used worldwide for children with intractable epilepsy
Freeman et al., 2007). It has been used to treat epilepsy inchildren since 1921 with little variation until recent years
Accepted June 20, 2008; Online Early publication xxxxxx xxxx.
(Freeman et al., 2007). The original protocol using a high
Address correspondence to Eric Kossoff, Suite 2158 - 200 North Wolfe
Street, The Johns Hopkins Hospital, Baltimore, MD, U.S.A. E-mail:
fat, low carbohydrate diet was created at the Mayo Clinic
in Rochester, MN (Wilder, 1921), and popularized by the
Johns Hopkins Hospital in Baltimore, MD (Freeman et al.,
C 2008 International League Against Epilepsy
1998). The KD was traditionally started in the hospital after
E. H. Kossoff et al.
a 48-h fast followed by a gradual introduction of calories
As comments and changes were received by all consen-
in the form of a KD over a 3-day period. Children were
sus members regarding details of the recommendations, it
then seen periodically in clinic for medical and nutritional
became clear that there were certain topics that were more
controversial than others. To convey these areas where con-
Over the past decade, however, there has been world-
sensus was not obtained, a short survey of 15 questions was
wide investigation into which children should be started on
then emailed to all 26 participants to obtain a group consen-
the KD, as well as the ideal protocol for its implementation
sus. Results from this survey were then incorporated into
and subsequent follow-up management. Unlike anticonvul-
the body of the manuscript, providing percentage responses
sant therapy, there are many ways in which to provide the
for topics. Following this, all participants later reviewed the
KD and each may be valid. With its inherent variability,
full manuscript again prior to submission. This consensus
there exists a need for standardized KD protocols both in
statement has been since endorsed by the Child Neurology
order to guide neurologists and dietitians beginning to of-
Society who also reviewed the full manuscript.
fer the KD in their individual centers as well as to guidemulticenter research studies. At this time, there are no in-
CONSENSUS RECOMMENDATIONS
ternational KD recommendations, with published attemptsmade on a national level in Germany only to date (Klepper
Patient selection
Most individuals who develop epilepsy will respond to
Recognizing that there is currently insufficient class I ev-
pharmacologic treatment, however, approximately 20%–
idence for the majority of the clinical management issues
30% will develop medically refractory epilepsy (Sillanp¨a¨a
regarding the KD to create a practice parameter (Hender-
& Schmidt, 2006). For this population, “alternative” or
son et al., 2006), The Charlie Foundation commissioned
nonpharmacologic treatments such as dietary therapy can
an international committee of neurologists and dietitians
be highly efficacious and should be seriously considered.
with expertise in the KD in December 2006 at the Amer-
In the past, the use of the KD was limited by the scarcity
ican Epilepsy Society meeting in San Diego, CA, U.S.A.
of centers experienced in its use as well as lack of confi-
The charge of this consensus group was to provide practi-
dence in the diet’s efficacy (Freeman et al., 2007). How-
cal recommendations to guide management of the KD.
ever, over the past decade the role of the KD in the treat-ment of intractable epilepsy has become evident from theincreased number of publications available as well as the
increased number of epilepsy centers that offer the KD
(Kossoff & McGrogan, 2005; Henderson et al., 2006; Free-
Experts in the clinical use of the KD were identified by
Jim Abrahams, founder of The Charlie Foundation, Beth
The KD can effectively treat epilepsy in individuals from
Zupec-Kania, RD, CD, Dietitian for The Charlie Founda-
infancy through adulthood. For years it was thought that
tion, and Eric Kossoff, MD, Medical Director of the Johns
infants have difficulty maintaining ketosis while meeting
Hopkins Ketogenic Diet Center. Identified clinicians had at
their growth requirements, and they therefore were not rou-
least one authored, peer-reviewed publication regarding the
tinely treated with the diet (Nordli et al., 2001). Adoles-
KD or were a member of a center that had published about
cents and adults have typically not been considered can-
the KD. Attempts were made to avoid more than three clin-
didates for KD treatment, although data for its benefit in
icians from any individual center. Twenty-six clinicians, of
these populations does exist (Barborka, 1930; Sirven et al.,
which seven (27%) were dietitians, were identified. Eleven
1999; Mady et al., 2003; Kossoff et al., 2008a). When sur-
(42%) participants were from outside the U.S.A. Dr. Kos-
veyed, 10 (38%) of the consensus group offered dietary
soff and the other 24 experts (other than Ms. Zupec-Kania)
therapy to adults. Regardless of age, seizure type, or eti-
did not receive direct funds from The Charlie Foundation
ology, the KD appears to provide a third of the patients
nor was this consensus statement subsidized in any way.
with >90% reduction in their seizure frequency (Hender-
Participants were asked to write a section topic either
individually or in pairs based on both their individual ex-
Traditionally, the KD has been reserved as a “last
pertise and an outline of clinical issues created by the two
treatment option” after establishment of medical in-
primary authors (E.K. and B.Z.K.). Instructions were given
tractability, typically defined as the failure of three or
to keep each section brief (2–3 paragraphs) and focus pri-
more anticonvulsant medications. Given its efficacy, the
marily on peer-reviewed publications when available. In
poor chance of improvement with further anticonvul-
the absence of published literature, the participants were
sant trials, and the availability of more easily imple-
asked to base recommendations on their professional or
mented alternatives such as the modified Atkins diet
center’s experience. Sections were collected (by E.K.), in-
(Kossoff et al., 2006) and Low Glycemic Index Treat-
corporated into a full document, and then emailed to the
ment (LGIT) (Pfeifer & Thiele, 2005), we propose that
dietary therapy be considered earlier as an option for
Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xConsensus Statement for the Ketogenic DietTable 1. Epilepsy syndromes and conditionsTable 2. Contraindications to the use of the KDin which the KD has been reportedas particularly beneficial
Probable benefit (at least two publications)
Carnitine palmitoyltransferase (CPT) I or II deficiency
Glucose transporter protein 1 (GLUT-1) deficiency
Myoclonic-astatic epilepsy (Doose syndrome)
Medium-chain acyl dehydrogenase deficiency (MCAD)
Long-chain acyl dehydrogenase deficiency (LCAD)
Short-chain acyl dehydrogenase deficiency (SCAD)
Severe myoclonic epilepsy of infancy (Dravet syndrome)
Medium-chain 3-hydroxyacyl-CoA deficiency.
Children receiving only formula (infants or enterally fed patients)
Suggestion of benefit (one case report or series)
Surgical focus identified by neuroimaging and video EEG monitoring
Subacute sclerosing panencephalitis (SSPE)
Preliminary experience also showing some beneficial
treatment of difficult-to-manage epilepsy. When surveyed,
effects of the KD have been reported in symptomatic
81% of the group believed that the KD should be
epilepsies due to Lafora body disease (Cardinali et al.,
offered to a child after two anticonvulsants are used
2006), Rett syndrome (Haas et al., 1986; Liebhaber et al.,
2003; Giampietro et al., 2006), Landau-Kleffner syndrome
There are several specific conditions in which the group
(Bergqvist et al., 1999), and subacute sclerosing panen-
considered the KD could be used potentially even earlier
cephalitis (Bautista, 2003). Single reports describe the use
(Table 1). The diet is the treatment of choice for two dis-
of the diet in metabolic disorders such as phosphofructok-
tinct disorders of brain energy metabolism: GLUT1 de-
inase deficiency (Swoboda et al., 1997), glycogenosis type
ficiency syndrome (Klepper & Leiendecker, 2007) and
V (Busch et al., 2005), and mitochondrial respiratory chain
pyruvate dehydrogenase deficiency (PDHD) (Wexler et al.,
complex disorders (Kang et al., 2007a).
1997). In GLUT1 deficiency syndrome, glucose trans-
The KD is contraindicated in several specific disorders
port across the blood-brain barrier is impaired resulting
(Table 2). The metabolic adaptation to the KD involves a
in seizures, developmental delay, and a complex move-
shift from use of carbohydrates to lipids as the primary
ment disorder (Klepper & Leiendecker, 2007). Twenty-
energy source. As such, a patient with a disorder of fat
four members of the consensus (92%) believed the KD
metabolism might develop a severe deterioration in the set-
should be considered as a first-line therapy for GLUT1
ting of fasting or a KD. Therefore, before initiating the KD,
deficiency syndrome. In PDHD, a severe mitochondrial
a child must be screened for disorders of fatty acid trans-
disease with lactic acidosis and severe impairment, pyru-
vate cannot be metabolized into acetyl-CoA (Wexler et al.,
Long-chain fatty acids are transported across the mito-
1997). In both disorders, the KD provides ketones that by-
chondrial membrane by carnitine, facilitated by carnitine
pass the metabolic defect and serve as an alternative fuel to
palmitoyltransferase (CPT) I and II and carnitine translo-
case (Tein, 2002). Once in the mitochondrion, fatty acids
The KD has also been described as particularly useful
are β-oxidized to two carbon units of acetyl-CoA that can
for certain epilepsy and genetic syndromes as well. My-
then enter the tricarboxylic acid cycle and be utilized for
oclonic epilepsies, including severe myoclonic epilepsy
energy production or ketone body formation. An inborn
of infancy (Dravet Syndrome) and myoclonic-astatic
metabolic error at any point along this pathway can lead to
epilepsy, as described by Doose (Oguni et al., 2002;
a devastating catabolic crisis (i.e., coma, death) in a patient
Laux et al., 2004; Caraballo et al., 2005, 2006; Kilaru &
fasted or placed on a KD. Deficiency of pyruvate carboxy-
Bergqvist, 2007; Korff et al., 2007) appear to respond well
lase, a mitochondrial enzyme that catalyzes the conversion
to the KD. The KD can be beneficial in infants with West
of pyruvate to oxaloacetate, will impair tricarboxylic acid
syndrome who are refractory to corticosteroids and other
cycle function and energy production in patients on the
medications (Nordli et al., 2001; Kossoff et al., 2002b; Eun
KD. Finally, the KD is contraindicated in porphyria, a dis-
et al., 2006). There is evidence from three epilepsy centers
order of heme biosynthesis in which there is deficient por-
for the benefits of the KD in tuberous sclerosis (Kossoff
phobilinogen deaminase; the lack of carbohydrates in the
et al., 2005; Coppola et al., 2006a; Kossoff et al., 2007c;
KD can exacerbate acute intermittent porphyria. Contrary
to prior anecdotal evidence, the KD has been reported in a
Epilepsia, **(*):1–14, 2008E. H. Kossoff et al.
single case series as safe and efficacious in mitochondrial
view all current medications to determine carbohydrate
diseases, mostly those with Complex I disease (Kang et al.,
content and options of switching to lower carbohydrate
Clinical suspicion about an inborn error of metabolism
Before starting the diet, it is crucial to also discuss
includes developmental delay, cardiomyopathy, hypotonia,
psychosocial issues inherent in the KD. The physician
exercise intolerance, myoglobinuria, and easy fatigability
should ensure that the parent or caregiver understands
(Sankar & Sotero de Menezes, 1999). The presence of one
their involvement in administering the KD to their child,
of those clinical features suggests that the child should be
specifically the importance of strict adherence to the diet,
tested to rule out an inborn error of metabolism prior to KD
avoidance of carbohydrates, need for multivitamin and
mineral supplementation, and awareness of potential ad-
Although not a true contraindication, there is recent ev-
verse effects. One should also identify any behavioral or
idence that children with very focal epilepsy may do less
personality traits in the child that will significantly chal-
well with the KD than resective surgery (Stainman et al.,
lenge successful administration of the diet and determine
2007). In this situation, the KD may offer a period of
any food allergies and intolerances and cultural/religious
both reduced seizures and anticonvulsants, but only rarely a
preferences that will need to be considered in meal
prolonged seizure-free response. The consensus group had
mixed opinion on whether to offer the KD for a child with a
Several laboratory studies are suggested before starting
clear surgically resectable lesion, with 15 (58%) providing
the KD (Table 3). If there is a personal or strong family
the KD in this situation as long as the family was ade-
history of kidney stones, a renal ultrasound and nephrol-
ogy consultation should be obtained. As part of the diag-
There are several uncontrolled trials and animal studies
nostic workup of a progressive epileptic encephalopathy,
describing the potential benefits of the KD for neurologic
cerebrospinal fluid evaluation (for glucose, protein, lac-
conditions other than epilepsy and the metabolic condi-
tate, folate metabolites, amino acids, and potentially neu-
tions described previously. These include amyotrophic lat-
rotransmitters) as well as a full serum and urine metabolic
eral sclerosis (ALS), Parkinson’s disease, Alzheimer’s dis-
evaluation should be performed if no clear etiology for the
ease, migraine, autism, narcolepsy, brain tumors, and trau-
child’s epilepsy has been identified. An electroencephalo-
matic brain injury (Freeman et al., 2007). At this time, there
gram (EEG) and magnetic resonance imaging (MRI) will
is insufficient evidence to recommend the use of the KD for
assist in identifying those patients who are possible sur-
these conditions other than on an investigational basis.
gical candidates; therefore, these investigations should bestrongly considered.
A key component of the KD is the information the fam-
The KD should be strongly considered in a child who
ily receives prior to the initiation of the diet. Many fami-
has failed two to three anticonvulsant therapies, regard-
lies will have preconceived notions about what the KD is,
less of age or gender, and particularly in those with symp-
how it will be initiated, and expectations of its efficacy,
tomatic generalized epilepsies. It can be considered the
especially since families have different experiences while
treatment of choice for two distinct disorders of brain
initiating the diet even within the same facility. Helpful re-
metabolism, GLUT-1 deficiency syndrome and PDHD. In
sources for families include The Ketogenic Diet: A Treat-
the particular epilepsy syndromes of Dravet syndrome, in-
ment for Epilepsy in Children and Others (Freeman et al.,
fantile spasms, myoclonic-astatic epilepsy, tuberous scle-
2006) and publications and videos from support groups
rosis complex, the KD could be offered earlier. The KD is
such as The Charlie Foundation and Matthew’s Friends.
probably only of limited benefit in children who are candi-
High glycemic carbohydrate foods can be reduced slightly
dates for epilepsy surgery. Before starting the KD, inborn
in advance of the KD to prepare the child for the dietary
errors of metabolism that could lead to a severe metabolic
crisis should be ruled out. These include disorders of fatty
It is important for the ketogenic team to thoroughly dis-
acid mitochondrial transport, β-oxidation, and other mito-
cuss parental expectations in advance of KD initiation to
ensure its success. Many families expect not only seizure
Prediet evaluation and counseling
reduction, but also medication reduction and cognitive im-
A clinic visit prior to initiation of the KD is neces-
provement (Farasat et al., 2006). The team should keep
sary and recommended. The goals of this visit are to iden-
the expectations realistic for each individual child. The ex-
tify the seizure type, rule out metabolic disorders that are
pected length of time on the KD if successful is often a
contraindications to the diet, and evaluate for complicat-
concern that the family wishes to discuss prior to start-
ing factors (presence of kidney stones, dyslipidemia, liver
ing the KD and a minimum of 3 months (to allow for po-
disease, failure to thrive, gastroesophageal reflux, poor
tential improvement to occur) should be suggested. The
oral intake, constipation, cardiomyopathy, and chronic
family should know what challenges they may face both
metabolic acidosis) (Table 3). The KD team should re-
short- and long-term, such as possible nausea, vomiting,
Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xConsensus Statement for the Ketogenic DietTable 3. Recommendations for pre-KD evaluation
Discuss seizure reduction, medication, and cognitive expectationsIdentify potential psychosocial barriers to the use of KDReview anticonvulsants and other medications for carbohydrate contentRecommend family read parent-oriented KD information
Baseline weight, height, and ideal weight for statureBody mass index (BMI) when appropriateNutrition intake history: 3-day food record, food preferences, allergies, aversions, and intolerancesEstablish diet formulation: infant, oral, enteral, or a combinationDecision on which diet to begin (MCT, classic, modified Atkins, or low glycemic index)Calculation of calories, fluid, and ketogenic ratio (or percentage of MCT oil)Establish nutritional supplementation products based on dietary reference intake
Complete blood count with plateletsElectrolytes to include serum bicarbonate, total protein, calcium, zinc, selenium, magnesium, and phosphateSerum liver and kidney tests (including albumin, AST, ALT, blood urea nitrogen, creatinine)Fasting lipid profileSerum acylcarnitine profileUrinalysisUrine calcium and creatinineAnticonvulsant drug levels (if applicable)Urine organic acidsSerum amino acids
Renal ultrasound and nephrology consultation (if a history of kidney stones)EEGMRICerebrospinal fluid (CSF) (if no clear etiology has been identified)EKG (echocardiogram) if history of heart disease
behavioral outbursts, and various other medical complica-
et al., 1989; Neal et al., 2008). In the classic KD, fat is
tions, and how to address these issues if they arise. A social
a LCT and obtained primarily from standard foods, protein
worker on the team can be instrumental in helping the fam-
is based on minimum requirements for growth, and carbo-
ily transition to the KD by assessing family needs, gather-
hydrates are restricted. MCT oils yield more ketones per
ing resources, and contacting other families on the KD for
kilocalorie of energy than their long chain counterparts;
they are absorbed more efficiently and carried directly to
It is also important for the family to know what to ex-
the liver. This increased ketogenic potential means less to-
pect during the hospital stay, such as whether tests (such as
tal fat is needed in the MCT diet, thus allowing inclusion of
EEG) or medical interventions (such as intravenous fluids)
more carbohydrate and protein. Data from studies 20 years
are likely. Parents are allowed to bring games and books
apart now suggest no difference in efficacy between the
to help keep the child comfortable during this time. Topics
two diets if applied appropriately in a calculated fashion
including meal preparation, managing sick days, traveling,
(Schwartz et al., 1989; Neal et al., in press). There may
celebrations, and nutritional supplements can be discussed
be some differences in tolerability but this did not reach
statistical significance in a recent randomized controlledtrial with direct comparison between the two (Neal et al.,
There are several important prerequisites to starting the
The classic KD is calculated in a ratio of grams of fat
KD to ensure both safety and to maximize the chances of
to grams of protein plus carbohydrate. The most common
ratio is 4 g of fat to 1 g of protein plus carbohydrate
Specific diet selection and provision
(described as “4:1”). This means that 90% of the energy
There has often been discussion as to whether there is
comes from fat and 10% from protein and carbohydrate
an optimal way to administer the KD. The classic (long
combined. Sometimes it is necessary to provide the KD
chain triglyceride or LCT) diet has been the more tradi-
at a lower ratio to increase protein or carbohydrate intake.
tional KD treatment, for which most data are available,
There is some evidence that a 4:1 ratio, when used at ini-
but the medium chain triglyceride (MCT) diet may be
tiation, may be more advantageous for the first 3 months
preferable in some cases (Huttenlocher, 1976; Schwartz
Epilepsia, **(*):1–14, 2008E. H. Kossoff et al.
Calories are typically restricted to 80%–90% of the daily
emulsion such as Microlipid (Nestle, Vevey, Switzerland)
recommendations for age; however, this has never been
to add the needed fat to achieve the goal KD ratio. In addi-
shown in patients to be beneficial (Vaisleib et al., 2004).
tion, water must be added to Ross Carbohydrate Free for-
Additionally, an underweight child should be started at
mula for proper dilution. Both combinations are fortified
calories based on current weight then increased gradu-
with vitamins and minerals; however each should be com-
ally over time. An overweight child should be allowed to
pared to age-appropriate requirements and supplemented
grow to appropriate length for weight rather than incurring
to meet the Dietary Reference Intakes (DRI) established
weight loss, although in some children attaining a more
by the National Academy of Sciences. In addition, a for-
ideal body weight may be nutritionally indicated. Simi-
mula may also be created from pureed infant foods with the
larly, fluid restriction to 90% is also based on historical use
addition of a liquid fat source, diluted with water, and sup-
of the diet rather than on scientific evidence. Many centers
plemented with micronutrients. This formula may be nec-
no longer fluid restrict children on the KD.
essary when allergies to both soy and milk protein formulas
The traditional MCT diet comprises 60% energy from
MCT. This level of MCT can cause gastrointestinal dis-
In the past few years, two other dietary therapies have
comfort in some children, with reports of abdominal
been developed for the treatment of epilepsy: the modi-
cramps, diarrhea, and vomiting. For this reason, a mod-
fied Atkins diet and LGIT (Pfeifer & Thiele, 2005; Kossoff
ified MCT diet was developed, using 30% energy from
et al., 2006; Kang et al., 2007b; Kossoff et al., 2007b). Un-
MCT, with an additional 30% energy from long chain fat.
like the classic KD, both of these dietary therapies are ini-
In practice, a starting MCT level somewhere between the
tiated without an inpatient hospital stay and they do not
two (40%–50% energy) is likely to be the best balance be-
require precise weighing of food ingredients and portions.
tween gastrointestinal tolerance and good ketosis. This can
Both diets require less dietitian time for meal calculations,
be increased or decreased as necessary during fine-tuning;
but more parental independence. All but one member of the
many children will tolerate 60% or higher energy from
consensus group (96%) offers these diets to children.
MCT and need this amount for optimum ketone levels and
The modified Atkins diet is similar to the classic KD in
seizure control. MCT oil has also been used to augment the
its composition and is approximately a 1:1 ketogenic ratio
traditional KD to stimulate ketones and for its beneficial
(Kossoff et al., 2006). The initial daily carbohydrate con-
laxative property. MCT can be given in the diet as oil, as
sumption on the modified Atkins diet is approximately 10
coconut oil, or as an emulsion (Liquigen, SHS, Liverpool,
g (comparable to the strict initiation phase of the Atkins
U.K.). MCT should be included in all meals when used.
diet used for weight loss), with a planned increase to 15–
Less quantity of MCT with each meal, with more meals
20 g/day after 1–3 months (Kossoff et al., 2007b). How-
ever, there are no limitations on protein, fluids, and calo-
The KD may be delivered as an all-liquid, formula-based
diet (Kossoff et al., 2004a; Hosain et al., 2005). Tolera-
The LGIT was developed following the observation that
bility and adverse effects of the KD in infants is similar
children on the classic KD have stable blood glucose lev-
to that in older children. The KD may also be easily ad-
els and the hypothesis that this may relate at least in part
ministered to enterally fed children. As expected, enter-
to the mechanism of the KD (Pfeifer & Thiele, 2005).
ally (including gastrostomy and jejunostomy) fed children
The LGIT allows liberalization of total daily carbohydrate
demonstrate very high compliance rates, exceeding those
intake to approximately 40–60 g/day, but regulates the
in most solid food KD series, and efficacy is also high
type of carbohydrate, favoring those that produce relatively
(Kossoff et al., 2004a; Hosain et al., 2005). Prescription
small changes in blood glucose (those with low glycemic
of a formula-based KD is generally simpler for dietitians
to calculate, requires less education of families and care-
Small, uncontrolled reports suggest that both modified
givers, and due to the ease of delivery of an all-liquid KD,
diets show efficacy rates similar to the classic KD. These
ketosis is easily maintained as errors are less common.
diets may also be of value for adolescents and adults not
To prepare a formula-based KD, three commercial prod-
typically offered the traditional KD. In fact, 11 (42%) of
ucts are currently available. KetoCal (for North America:
the consensus group believed these diets should be used
Nutricia, Rockville, MD, U.S.A. and for Europe: SHS) is
primarily when treating adolescents. Larger, randomized
a milk protein-based, powdered formula to which water
studies are needed to better understand the efficacy and
is added. This provides either a 3:1 or 4:1 KD; however,
tolerability of these diets, how they compare to the clas-
fat and protein modulars may be added to customize the
sic KD, and potential use in adults.
diet for each child. Ross Carbohydrate Free Soy FormulaBase With Iron (Abbott Nutrition, Columbus, OH, U.S.A.),
which provides protein, some fat, and vitamins and miner-
There is no evidence of increased efficacy of MCT ver-
als, may also be combined with a carbohydrate polymer
sus LCT, therefore which KD is chosen should be based
such as Polycose powder (Abbott Nutrition), and a lipid
on the dietary needs and habits of the individual child,
Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xConsensus Statement for the Ketogenic Diet
although it may be influenced by the experience of the
(58%) members believed fasting was not necessary but did
team involved. An all-liquid, formula-based KD is recom-
have benefit, eight (31%) did not believe fasting should be
mended for use in infants who have not yet transitioned to
used, and three (11%) stated that fasting should be univer-
solid foods and for individuals fed enterally. There is pre-
liminary evidence for the use of both the less restrictive
The main reasons for inpatient initiation include safety
modified Atkins diet and LGITs, but the optimal patient
(management of acute medical side effects) and education
populations for these diets have not yet been identified.
of care providers. Twenty-three members (88%) routinely
These latter two therapies may be advantageous for ado-
admit children for initiation of the KD. However, it is pos-
sible to start the KD as an outpatient, based on two retro-spective studies encompassing 8 and 37 patients, respec-
Diet initiation
tively, in which no fasting period was used (Wirrell et al.,
The KD initiation practices have their origin in the
2002; Vaisleib et al., 2004). Although there were no serious
historical use of periodic fasting to treat seizures. Fast-
side effects related to unmasking an underlying metabolic
ing is therefore part of the KD initiation in many centers
disorder with an outpatient approach, the size of these
worldwide. Because of concerns that fasting may result
samples is too small to expect discovery of relatively rare
in hypoglycemia, acidosis, nausea, vomiting, dehydration,
anorexia, lethargy, and a small risk for increase in seizures,
The potential advantages of an outpatient, gradual KD
most centers begin the KD in the hospital so that the patient
initiation include less stress for the child, no absence
can be closely observed, and medical interventions can be
from the home for the care providers, and significantly re-
instituted if necessary. Hospitalization also provides the
duced costs associated with hospitalization. However, to
opportunity for intensive teaching of the caregivers on how
provide the KD initiation as an outpatient, all children
to calculate, weigh, design meals, and manage the KD at
must be screened completely prior to starting the KD with
metabolic testing, the child must be in close proximity to
The traditional method of initiating the KD involves a
medical care, and the KD team must be able to provide all
period of fasting, with no carbohydrate-containing fluids
the family education in an outpatient setting. Although as
provided, and serum glucose monitored periodically (Free-
stated previously, most centers still routinely admit for KD
man et al., 2006). The duration of fasting varies from 12 h
initiation, 19 (73%) members believed that an outpatient
to “when urine ketones are large,” which can be longer than
initiation could be used in very select situations.
48 h. Children should not be fasted longer than 72 h. The
meals are then typically advanced daily in one-third caloric
At this time, there is evidence that the traditional KD
intervals until full calorie meals are tolerated, while keep-
protocol can be altered successfully to ease its implemen-
ing the KD ratio constant. Another approach begins with
tation. Fasting may be appropriate when a quicker time to
full calories, but the KD ratio increases daily from 1:1, 2:1,
response is desired, but is not necessary for long-term effi-
3:1, to 4:1 to allow the patient to acclimate to the increasing
cacy, and may have more immediate side effects. In select
concentration of fat (Bergqvist et al., 2005).
situations, the KD can also be started as an outpatient.
In most clinical trials of KD efficacy, a fasting initia-
tion protocol was used. However, there is now retrospec-
Medications and the KD
tive (Kim et al., 2004) and prospective data indicating that
The KD is traditionally used in patients who have failed
fasting is not necessary for achievement of ketosis, and that
to respond to anticonvulsant medications. Specifically, it is
gradual initiation protocols offer the same seizure control
customary to add the KD to an existing regimen of drugs.
at 3 months with significant lower frequency and sever-
Hence, with the exception of patients whose drugs are
ity of initiation related side effects (Bergqvist et al., 2005).
eventually discontinued due to an excellent response to the
In addition, weight loss, hypoglycemia, and acidosis were
KD, little is known about both the efficacy and tolerability
less common when children were not fasted in this study
of the KD without the confound of concomitant medica-
(Bergqvist et al., 2005). Vomiting did not differ in the
tions. Surprisingly, despite decades of combined use of an-
two protocols, but intravenous fluids for dehydration were
ticonvulsants and the KD, it remains unclear whether there
more commonly needed in the fasting group. Continued
are negative or positive pharmacodynamic interactions, and
use of fasting protocols is therefore based on the centers’
only scant information regarding the impact of the KD on
individual practice rather than a need for seizure control.
the pharmacokinetics of anticonvulsants.
Some older as well as recent evidence suggests that fast-
At present, there are no data supporting any signifi-
ing does lead to a quicker onset of seizure reduction, and
cant pharmacodynamic interactions between anticonvul-
therefore may be advantageous when a more immediate re-
sant drugs and the KD. That is, no particular combination
sponse is desired (Freeman & Vining, 1999; Kossoff et al.,
of anticonvulsants and the KD have been shown to yield
2008b). There was a difference of opinion between mem-
either greater or less efficacy in terms of seizure protec-
bers of the consensus group in regards to fasting. Fifteen
tion at this time. The KD may have synergistic benefits
Epilepsia, **(*):1–14, 2008E. H. Kossoff et al.
when used in combination with a nonpharmacologic ther-
1976). Clinicians should be mindful that formulations of
apy; namely vagus nerve stimulation (VNS) (Kossoff et al.,
many drugs, including nonanticonvulsants, contain carbo-
2007a). Serum levels of commonly used anticonvulsant
hydrates or sugars as additives (Lebel et al., 2001), and
agents, when corrected for changes in dose and weight (i.e.,
should seek alternatives whenever possible.
plasma concentration in relation to the dose per kilogram
of body weight per day), do not appear to be altered by the
At this time, there is little evidence of any consistent pos-
itive interactions between the KD and anticonvulsants. The
There is a historical perception that valproic acid should
KD may work well in combination with VNS. Conversely,
not be used together with the KD. This stems from the con-
the KD is not negatively affected in regards to efficacy or
cerns for idiosyncratic side effects of valproic acid (i.e.,
side effects by any particular anticonvulsant. Medications
hepatotoxicity) and for the fact that this medication is a
can often be reduced within the first few months if the KD
short-chain fatty acid. Clinicians have generally feared that
is successful, although caution is advised especially when
enhanced fatty acid oxidation, a consequence of using the
reducing phenobarbital and benzodiazepines.
high-fat KD, might increase the risk of hepatotoxicity. De-
Diet supplementation
spite such fears, recent clinical evidence supports the safe
Sufficient vitamins and minerals are normally found in
use of valproic acid and the KD (Lyczkowski et al., 2005).
a well-balanced diet, however due to the limited quanti-
But while idiosyncratic adverse reactions are not neces-
ties of fruits, vegetables, enriched grains, and foods con-
sarily heightened, it does appear that secondary carnitine
taining calcium on the KD, supplementation is essential,
deficiency, which can occur with either the KD or valproic
especially for B vitamins (Table 4). There is little vitamin
acid alone, can be worsened (Coppola et al., 2006b).
D and calcium in KD food and evidence for decreased Vi-
The KD is also known to cause a transient but often clin-
tamin D levels in children with epilepsy, and therefore both
ically asymptomatic metabolic acidosis. Adding the KD
vitamin D and calcium should be supplemented (Bergqvist
to an existing regimen of carbonic anhydrase inhibitors
et al., 2007). Additional supplementation (e.g., zinc, se-
(topiramate and zonisamide) may in fact worsen preexist-
lenium, magnesium, phosphorus) was suggested by some
ing metabolic acidosis, but the greatest decreases in serum
group members, but at this time there is insufficient evi-
bicarbonate levels occur early after initiation of the diet
dence to recommend their use above what is provided in a
(Takeoka et al., 2002). It is recommended that bicarbonate
levels should be monitored carefully, especially when re-
Carbohydrate-free or minimal carbohydrate-containing
ceiving these anticonvulsants, and that bicarbonate supple-
multivitamin and mineral products should be used. Some
ments be given when patients are clinically symptomatic
vitamins and supplements that will be discussed may
(vomiting, lethargy). There may be health benefits, specifi-
have limited availability based on individual country. In
cally to bone density, in the use of bicarbonate supplements
the U.S., commonly used preparations include Centrum
for children with acidosis, but this has not been proven. It
(Wyeth, Madison, NJ, U.S.A.) and Bugs Bunny Sugar-free
does not appear that carbonic anhydrase inhibitors, which
(Bayer, Morristown, NJ, U.S.A.). Multibionta (Seven Seas,
can increase the risk of kidney stones separately, have an
Marfleet, U.K.) is a multivitamin supplement also available
increased likelihood of stones when used in combination
as a liquid formulation. A relatively new vitamin designed
with the KD (Kossoff et al., 2002a). However, it is wise to
for the KD and allergy population is called NanoVM
observe children for stones more carefully when on car-
(Solace Nutrition, Rockville, MD, U.S.A.). This product
bonic anhydrase inhibitors and perhaps empirically startoral citrates such as Polycitra K (Cypress Pharmaceuticals,Madison, MS, U.S.A.) (Sampath et al., 2007). There is no
Table 4. Supplementation recommended
evidence for routine renal ultrasound surveillance, how-
for children receiving the KD
ever, or automatic discontinuation of these anticonvulsants
Multivitamin with minerals (and trace minerals)
Discontinuing medications is often a major goal of the
KD and typically advised after several months of success.
However, there is evidence that anticonvulsants can be re-
Oral citrates (Polycitra K)Laxatives: Miralax, mineral oil, glycerin suppository
duced successfully even during the first month of the KD
Additional selenium, magnesium, zinc, phosphorus, vitamin D
(Kossoff et al., 2004b). Seizure exacerbations are more
likely when phenobarbital or benzodiazepines are the an-
ticonvulsants weaned, so caution is recommended when
Salt (sodium to add to modular formulas if used for greater
Finally, ingestion of carbohydrates can quickly reverse
All supplements listed should be provided as carbohydrate-
the ketosis achieved by the KD in some children and
free preparations whenever possible.
may lead to resumption in seizure activity (Huttenlocher,
Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xConsensus Statement for the Ketogenic Diet
is virtually carbohydrate-free, is formulated to meet 100%
be preventative for kidney stones, but its empiric use has
of the micronutrient needs of children, and is available in
not yet been established as beneficial.
two preparations for ages 1–3 and 4–8 years.
There is evidence for the preventative use of oral cit-
Maintenance of children receiving the KD
rates (Polycitra K more so than Bicitra) in regards to reduc-
The child on the KD should be seen regularly for follow-
ing the risk of kidney stones. In a retrospective study, the
up evaluation by both dietitian and neurologist familiar
risk was reduced three-fold with their use; many children
with the KD (Table 5). At discharge, the parents should be
who presented with renal stones in this study had not been
given specific contact phone numbers and e-mail addresses
started on Polycitra K, despite occasionally borderline ele-
for the KD team, especially the dietitian. The child should
vations in their urine calcium to creatinine ratio (Sampath
be seen initially at least every 3 months after hospital dis-
et al., 2007). The empiric use of citrates in all children on
charge with follow-up contact in the interim, especially if
the KD may be sensible, but has not been tested prospec-
expected urinary ketosis is not maintained. A child under
tively in a controlled manner for kidney stone prevention.
1 year of age may be seen back in 2–4 weeks and should
Citrates may also reduce acidosis and theoretically bone
have more frequent contact with the KD team. Other chil-
mineral loss; however, there is evidence that folic acid ab-
dren that may require extra attention include those with
sorption is reduced in an alkaline environment induced by
cerebral palsy, whose growth parameters are at or less than
bicarbonate use, which may increase the risk for mega-
the fifth percentile, and any child with continued difficulty
loblastic anemia (Benn et al., 1971).
consuming the KD or with an illness shortly after KD ini-
Gastrointestinal dysmotility can be a common side effect
tiation. After 1 year on the KD, visits can be spaced out to
of the KD; however, empiric supplementation to alleviate
every 6 months with phone contact in the interim.
this has not been studied. Children are often started on H2-
At this time, the majority (96%) of the consensus group
blockers or proton pump inhibitors for gastroesophageal
advocates routine urine ketosis evaluation by parents sev-
reflux, but most commonly after this condition occurs.
eral times per week. There is limited data regarding the
Constipation is even more common on the KD, and par-
value of serum β-hydroxybutyrate (BOH), with one study
ents should be aware of prevention techniques including
suggesting that serum BOH may better correlate with
the use of higher fiber vegetables, sufficient fluids, and if
seizure control (Gilbert et al., 2000). Many members of
necessary, the use of carbohydrate-free laxatives.
the consensus group believed that obtaining serum BOH at
Carnitine supplementation has been a controversial is-
routine KD clinic visits was valuable, but only four (15%)
sue, with variability in its use between many centers world-
suggested parents use home BOH meters. It is reasonable
wide. Secondary hypocarnitinemia can cause serious sys-
to obtain serum BOH in clinical situations where urine ke-
temic complications such as hepatitis and cardiomyopathy,
tosis does not correlate with expected seizure control (e.g.,
although the incidence is quite low (Berry-Kravis et al.,
absent urinary ketosis despite seizure freedom or large uri-
2001). Relatively common symptoms indicating hypocar-
nary ketosis in the setting of worsening seizures).
nitinemia are generalized weakness, excessive fatigue, and
In addition to a complete examination, including accu-
decreased muscle strength, which are common in many pa-
rate growth parameters such as weight and height, labora-
tients with intractable epilepsy. Prolonged use of anticon-
tory studies are recommended. Special attention is given
vulsants such as valproic acid, poor nutritional status, and
to serum albumin and total protein concentration to ensure
long-term use of KD are the causes of secondary hypocar-
the KD is providing enough protein and calories. Fasting
nitinemia, especially in younger patients (Coppola et al.,
cholesterol and triglyceride levels typically rise and should
2006b). Laboratory measurement of serum carnitine is not
be monitored. Decisions regarding withdrawal of anticon-
easily feasible in some countries. Carnitine supplementa-
vulsants depends on the child’s response to the diet (see
tion may also be expensive if not covered by insurance
previous section). The majority of centers do not obtain
and adds an additional medication that is often dosed three
routine renal or carotid ultrasounds, echocardiograms, or
times a day. Seventy-seven percent of the consensus group
bone mineral density evaluations. Nine (35%) consensus
obtains baseline carnitine levels, and 81% check levels at
members routinely check an EEG after several months on
follow-up visits. The majority recommends that carnitine
should only be supplemented orally if either levels are low
While receiving the KD, there needs to be ongoing nutri-
(65%) or children become symptomatic (27%).
tional support and management. Caloric intake and growthparameters should be reviewed at least every 3 months forthe first year on the KD to ensure appropriate weight gain
for age and length. Infants under 1 year of age should be
There is evidence for the use of low-carbohydrate multi-
monitored more frequently to prevent growth disturbance
vitamin and mineral supplements in the routine use of the
(Vining et al., 2002). If a child is overly hungry or not eat-
KD. There is no evidence for the empiric use of antacids,
ing their meals, calories should be adjusted accordingly.
laxatives, or carnitine with the KD. Oral citrates appear to
There is no evidence that excessive weight gain or loss
Epilepsia, **(*):1–14, 2008E. H. Kossoff et al.Table 5. Recommendations for aspects of a follow-up KD clinic visita
Nutritional assessment (registered dietitian)
Obtain height weight, ideal weight for stature, growth velocity, BMI when appropriateReview appropriateness of diet prescription (calories, protein, and fluid)Review vitamin and mineral supplementation based on dietary reference intake guidelinesAssess compliance to therapyAdjust therapy if necessary to improve compliance and optimize seizure control
Efficacy of the diet (is the KD meeting parental expectations?)Anticonvulsant reduction (if applicable)Should the KD be continued?
Complete blood count with plateletsElectrolytes to include serum bicarbonate, total protein, calcium, magnesium, and phosphateSerum liver and kidney profile (including albumin, AST, ALT, blood urea nitrogen, creatinine)Fasting lipid profileSerum acylcarnitine profileUrinalysisUrine calcium and creatinineAnticonvulsant drug levels (if applicable)
Serum β-hydroxybutyrate (BOH) levelZinc and selenium levelsRenal ultrasoundBone mineral density (DEXA scan)EEG
aVisits should be at least every 3 months for the first year of the KD.
adversely affects KD effectiveness for seizure control,
on appropriate fluid volume as a daily goal. If appropriate
fluid intake cannot be met, a urine specific gravity within
The ketogenic ratio for the classic KD and percentage
normal limits (<1.015) is a good measure of adequate
MCT oil for the MCT diet may also be adjusted upwards
in the case of decreased ketosis and loss of seizure con-
At each clinic visit, but definitely according to the con-
trol, and lowered in situations of diet intolerability, severe
sensus group after a median of 2 years (range: 0.5–4
dyslipidemia, poor linear growth, or excessive ketosis re-
years), a thorough reevaluation of the KD risks and benefits
sulting in lethargy. A single study evaluating a planned de-
should be considered. Parents should be allowed a primary
crease from a 4:1 to 3:1 ratio after 3 months found no loss
decision-making role in deciding how long to maintain the
of seizure control by this change or significant improve-
KD for their child unless there are clear medical concerns.
ment in seizure control by increasing the ratio (Seo et al.,
2007). Ratios higher than 4.5:1 are generally not used for
Ongoing clinic visits at least every 3 months for the first
more than a few months, because of the increased risk of
year with ready access to experienced advice are important
adverse effects and poor compliance. Lowering the ratio to
for successful management of children receiving the KD.
2:1 or 1:1 can be implemented for children who are expe-
More frequent visits may be necessary for infants and other
riencing extreme difficulties adhering to the stricter ratios,
patients at high risk for nutritional deficiency. All children
particularly older adolescents and teenagers. Liberalizing
should be seen by an experienced pediatric neurologist and
the diet in this manner is similar to implementing the low
dietitian and have a nutritional assessment, laboratory eval-
glycemic index or modified Atkins approaches (Pfeifer &
uation, and discussion regarding KD and anticonvulsant
Thiele, 2005; Kossoff et al., 2006).
Liberalization of fluid should be considered for patients
at increased risk for dehydration, such as those with in-
Adverse effects of the KD
creased activity, febrile illness, or exposure to warm tem-
Although there have been numerous clinical trials of the
peratures, as well as infants. Low carbohydrate diets have
KD, adverse events have not been consistently reported
a diuretic effect and in addition, unlike a normal diet, the
in these studies. However, side effects of the diet do oc-
contribution of fluid from the restricted volume of foods in
cur, and neurologists and dietitians need to be observant
the KD is minimal. It is helpful for families to be counseled
(Ballaban-Gil et al., 1998; Wheless, 2001).Epilepsia, **(*):1–14, 2008doi: 10.1111/j.1528-1167.2008.01765.xConsensus Statement for the Ketogenic Diet
Metabolic abnormalities are relatively minor side effects
of the KD and include hyperuricemia (2%–26%), hypocal-
Like all medical therapies, the KD has potential adverse
cemia (2%), hypomagnesemia (5%), decreased amino acid
effects. Overall, the risk of serious adverse events is low,
levels and acidosis (2%–5%) (Schwartz et al., 1989; Ches-
and the KD does not need to be discontinued for these
ney et al., 1999; Kang et al., 2004). Gastrointestinal symp-
reasons for most children. However, physicians need to be
toms including vomiting, constipation, diarrhea, and ab-
aware of these potential risks so they can properly counsel
dominal pain occur in 12%–50% of children (Kang et al.,
parents and monitor children for the development of these
2004). Carnitine deficiency has also been demonstrated, as
described previously (Berry-Kravis et al., 2001). Hyperc-holesterolemia has been reported in 14%–59% of children
KD discontinuation
on the KD (Chesney et al., 1999; Kwiterovich et al., 2003;
The timing and actual method of KD discontinuation are
often individualized based on patient response to the diet.
Renal calculi occur in 3%–7% of children on the KD
Most parents are counseled to continue the KD, even if ap-
(Furth et al., 2000; Kossoff et al., 2002a; Sampath et al.,
parently ineffective, for at least 3 months (Freeman et al.,
2007). Stone composition includes uric acid (50% of
2006). The consensus group agreed that the KD should be
stones), calcium oxalate, calcium phosphate, and mixed
used for at least a mean of 3.5 months (SD 2.2 months) be-
calcium/uric acid stones. They typically do not require diet
fore considering discontinuation. Recent data suggests that
discontinuation and lithotripsy is only rarely necessary. As
the KD works rapidly when effective, with 75% of chil-
previously stated, Polycitra K appears to help prevent stone
dren responding within 14 days (Kossoff et al., 2008b),
so shorter KD durations may be adequate to assess effi-
There is conflicting data on the effect of the KD
cacy. Should seizures worsen for more than a few days af-
on growth in children. One retrospective review of lin-
ter starting the KD, similar to anticonvulsants, it could be
ear growth found that 86% of children on the diet had
discontinued immediately. If a family chooses to remain
slowed growth, and this effect was independent of mean
on the KD for longer than 6 months despite no apparent
age, length of time on the diet, or protein and energy in-
seizure control, the decision is ultimately their own and
take per body weight (Williams et al., 2002). A prospective
study of 237 children found that the while older children
In children with >50% seizure response, the KD is of-
grew “almost normally”; younger children grew poorly
ten discontinued after approximately 2 years; however, in
(Vining et al., 2002). There does not appear to be a differ-
children in whom seizure control is nearly complete (e.g.,
ence between diets used despite the greater protein content
>90% seizure reduction) and side effects are low, the diet
of the MCT diet (Neal et al., in press).
has been reported as helpful for as long as 6–12 years
Cardiac abnormalities have been reported, most anecdo-
(Groesbeck et al., 2006). This 2-year period is tradition-
tally, in children on the KD, including cardiomyopathy and
ally based on a similar time period used for anticonvul-
prolonged QT interval (Best et al., 2000; Bergqvist et al.,
sant drugs, which are often discontinued after that time in
2003; Kang et al., 2004). The mechanism of these compli-
children who become seizure-free. Children with GLUT-1,
cations is unknown; one case was associated with selenium
PDHD, or tuberous sclerosis complex may require longer
deficiency, but others were not. Pancreatitis has also been
KD durations than other conditions. Nineteen (73%) mem-
reported (Stewart et al., 2001; Kang et al., 2004).
bers routinely obtain an EEG prior to a planned KD dis-
The long-term complications in children maintained on
continuation. For those in whom the diet has led to seizure
the KD for greater than 2 years have not been systemat-
freedom, 80% of children will remain seizure-free after the
ically reviewed; there is only one report in the literature
diet has been discontinued (Martinez et al., 2007). How-
looking at this small subgroup (Groesbeck et al., 2006). In
ever, the risk of recurrence is higher in those with epilepti-
this population, there was a higher risk of bone fractures,
form EEGs, structural abnormalities on neuroimaging, and
kidney stones, and decreased growth, but dyslipidemia was
tuberous sclerosis complex (Martinez et al., 2007).
not identified (Groesbeck et al., 2006). It may be advan-
Although the diet can be discontinued abruptly in an
tageous in any child receiving the KD for long-term use,
emergency, typically in an intensive care unit, it is more of-
or anticonvulsants for that matter, to have periodic dual
ten tapered slowly over 2–3 months by gradually lowering
energy x-ray absorptiometry (DEXA) screening for bone
the ketogenic ratio from 4:1 to 3:1 to 2:1, then ketogenic
health. In particular, the long-term effects of this high-fat
foods are continued, but calories and fluids are increased
diet on the cardiovascular system remain to be determined.
ad libitum. Once urinary ketosis is lost, high carbohy-
There were no particular adverse effects that the consen-
drate foods can be reintroduced. This recommendation is
sus felt strongly should lead to automatic diet discontinu-
based on traditional practice patterns, and mimics the sev-
ation. All members believed that the adverse effects of the
eral week gradual wean of anticonvulsant drugs (Freeman
KD need to be considered always in comparison to its ben-
et al., 2006). During this time period, the group recom-
mends continued nutritional supplementation. If seizures
Epilepsia, **(*):1–14, 2008E. H. Kossoff et al.
worsen, the KD can be increased to the previously effective
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This work was presented at the International Symposium on Dietary
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support for research from Cyberonics. Dr. Kossoff has received support
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